title: The effects of testosterone deprivation and supplementation on proteasomal and autophagy activity in the skeletal muscle of the male mouse: differential effects on high-androgen responder and low-androgen responder muscle groups.
abstract: Men with prostate cancer who receive androgen deprivation therapy show profound skeletal muscle loss. We hypothesized that the androgen deficiency activates not only the ubiquitin-proteasome systems but also the autophagy and affects key aspects of the molecular cross talk between protein synthesis and degradation. Here, 2-month-old male mice were castrated and treated with either testosterone (T) propionate or vehicle for 7 days (short term) or 43 days (long term), and with and without hydroxyflutamide. Castrated mice showed rapid and profound atrophy of the levator ani muscle (high androgen responder) at short term and lesser atrophy of the triceps muscle (low androgen responder) at long term. Levator ani and triceps muscles of castrated mice showed increased level of autophagy markers and lysosome enzymatic activity; only the levator ani showed increased proteasomal enzymatic activity. The levator ani muscle of the castrated mice showed increased level and activation of forkhead box protein O3A, the inhibition of mechanistic target of rapamicyn, and the activation of tuberous sclerosis complex protein 2 and 5'-AMP-activated protein kinase. Similar results were obtained in the triceps muscle of castrated mice. T rescued the loss of muscle mass after orchiectomy and inhibited lysosome and proteasome pathways dose dependently and in a seemingly IGF-I-dependent manner. Hydroxyflutamide attenuated the effect of T in the levator ani muscle of castrated mice. In conclusion, androgen deprivation in adult mice induces muscle atrophy associated with proteasomal and lysosomal activity. T optimizes muscle protein balance by modulating the equilibrium between mechanistic target of rapamicyn and 5'-AMP-activated protein kinase pathways.
authors.affiliation: Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, Boston, MA 02115. cserra@partners.org.
authors.forename: Carlo
authors.initials: C
authors.lastname: Serra
authors.forename: Nicolae Lucian
authors.initials: NL
authors.lastname: Sandor
authors.forename: Hyeran
authors.initials: H
authors.lastname: Jang
authors.forename: Daniel
authors.initials: D
authors.lastname: Lee
authors.forename: Gianluca
authors.initials: G
authors.lastname: Toraldo
authors.forename: Tyler
authors.initials: T
authors.lastname: Guarneri
authors.forename: Siu
authors.initials: S
authors.lastname: Wong
authors.forename: Anqi
authors.initials: A
authors.lastname: Zhang
authors.forename: Wen
authors.initials: W
authors.lastname: Guo
authors.forename: Ravi
authors.initials: R
authors.lastname: Jasuja
authors.forename: Shalender
authors.initials: S
authors.lastname: Bhasin
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D056668:Cathepsin L / Q000235:genetics / Q000378:metabolism; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism*; D009919:Orchiectomy; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011897:Random Allocation; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D013739:Testosterone; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D056668:Cathepsin L; D046988:Proteasome Endopeptidase Complex